Alimta Sensitivity Correlates with Never- or Light-smoking, Not ALK+ Status - 1247227

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craig
craig's picture
Alimta Sensitivity Correlates with Never- or Light-smoking, Not ALK+ Status - 1247227

In past months, a couple of very interesting studies suggested that patients with ALK-driven cancer might be more likely than others to be super-responders to Alimta (pemetrexed). New research now suggests that might actually not have been a correlation directly with ALK+ status, and the incremental benefit might be a little less than previously thought.

== ALK+ Alimta-Sensitivity Hypothesis ==

The ALK+ super-responder hypothesis for Alimta was originated by Dr. Ross Camidge, the best "superdoc" in the Western states for ALK. Here's where you can read the abstract of that research:
"ALK Gene Rearrangements in NSCLC Are Associated with Prolonged Progression-Free Survival on Pemetrexed"
http://www.ncbi.nlm.nih.gov/pubmed/21336183

And a few months later, research from Korea seemed to confirm that pattern:
"ALK Translocation: A Predictive Biomarker of Pemetrexed in Patients with NSCLC"
http://www.ncbi.nlm.nih.gov/pubmed/21642865

Now we have this:

== The New Research ==

"Pemetrexed-based Chemotherapy in Patients with Advanced, ALK-positive NSCLC"
by Alice Shaw, MD, PhD and an international team with patient data from cancer centers in Boston, New York City, East Melbourne Australia, and Torino Italy.
http://www.ncbi.nlm.nih.gov/pubmed/22887466

The abstract concludes with:

- PFS on pemetrexed or non-platinum/pemetrexed combinations was similar in ALK-positive and ALK-negative patients.

- PFS on first-line platinum/pemetrexed may be prolonged in never/light-smoking patients regardless of ALK status.

(see below continuation in my reply to myself, due to the #characters-limit here.)

craig
craig's picture
Reply To: Alimta Sensitivity Correlates with Never- or Light

(. . . continuing . . . )
Here’s my takeaway notes from reading the full article:

- Alimta sensitivity appears to be better correlated with never-smoker/light-smoker (NS/LS) status than with ALK+ status.

- The responses seen in ALK+ patients and in NS/LS patients are a little shorter than previously reported, probably due to (1) the %mix of patients getting Alimta alone vs. with a platinum chemo vs. with a non-platinum chemo and/or (2) the %mix of patients getting Alimta as 1st line vs. 2nd or later line.

- The best incremental response to Alimta appeared to correlate with treatments which used both Alimta and platinum-based chemo (e.g., cisplatin or carboplatin) (7.3 month median PFS, 8.5 in 1st line), much longer than either Alimta plus non-platinum chemo (5.5 mo.) or Alimta alone (4.4 mo. in 1st line). Therefore the %mix of these variations can be significant to a calculation of an average.

- Alimta response duration was a little longer in 1st line treatment than 2nd or later lines of treatment by about a month. Therefore the %mix of 1st line vs. 2nd or later line can shift the calculation of an average by up to a month.

- The %mix of patients in any of these studies might also be affected by the fact that some cancer centers may attract more traveling patients who have characteristics making them more likely to respond longer. (I’d imagine examples might be being healthier in general or having a simpler or slower cancer.)

(see rest of this in next reply)

_________________________________
Stage 4 ROS1+ [mucinous BAC] adenocarcinoma NSCLC since 2011
Xalkori (crizotinib) 5 yrs
Alimta (pemetrexed) + carboplatin (mere months)
TPX-0005 (repotrectinib) TBD (1+ years as of Fall 2018)

craig
craig's picture
Reply To: Alimta Sensitivity Correlates with Never- or Light

(. . . continuing . . . )

- A very small amount of sidebar data was shown for the correlation of low thymidylate synthase (TS) level with longer response to Alimta. (Some researchers hypothesize that low TS might correlate with Alimta response and it’s often (usually?) low in adenocarcinoma, but usually high in squamous or SCLC). The two individuals with high TS had the shortest duration; those with low TS had a range of duration from weeks to years.

- Two large randomized phase III trials (already underway) should be able to add more data on this subject, and better than the retrospective study reported here.

Best hopes,

Craig

_________________________________
Stage 4 ROS1+ [mucinous BAC] adenocarcinoma NSCLC since 2011
Xalkori (crizotinib) 5 yrs
Alimta (pemetrexed) + carboplatin (mere months)
TPX-0005 (repotrectinib) TBD (1+ years as of Fall 2018)

Dr West
Reply To: Alimta Sensitivity Correlates with Never- or Light

I'll look forward to reading more, but thanks for bringing this to our attention.

-Dr. West

+++++++++++++++++++++++++
Dr. Howard (Jack) West
Associate Clinical Professor
Medical Oncology
City of Hope Cancer Center
Duarte, CA

Founder & President
Global Resource for Advancing
Cancer Education

denderdender
Reply To: Alimta Sensitivity Correlates with Never- or Light

Where may I find the mentioned Phase 3 studies on thymidylate synthase and Pemetrexed effectiveness?

craig
craig's picture
Reply To: Alimta Sensitivity Correlates with Never- or Light

[Re-edited Reply]

DenderDender,

That summary bullet point was not referring to the prior point about thymidylate synthase. The content underlying the bullet was this: "While there may be improved efficacy with front-line platinum/pemetrexed in ALK-positive and other never/light smoking patients, we believe pemetrexed-based chemotherapy is unlikely to be equivalent to crizotinib therapy in terms of efficacy. This question will be directly address in two ongoing randomized phase III trials. In the first-line trial, the comparator is platinum/pemetrexed, while in the second trial the comparator is either pemetrexed."

Neither alluded-to study was named as far as I can see, but I assume that one is probably one that was reported at the 2012 ESMO conference on Oct 1:
http://www.oncologystat.com/news/Crizotinib_Changes_Practice_for_Advance...
This study refers to the PROFILE 1007 study, and found . . . "crizotinib (Xalkori) remained superior regardless of whether chemotherapy contained docetaxel (Taxotere) (7.7 vs. 2.6 months, ...) or pemetrexed (Alimta) (7.7 vs. 4.2, ...). (This is in contrast to some gov't policies that preferred Alimta prior to crizotinib.)

Best hopes,

Craig

PS -- FYI, if you are interested in learning more about thymidylate synthase (TS) as possible indicator of possible Alimta effectiveness, I recommend the NIH's PubMed database search function:
http://www.ncbi.nlm.nih.gov/pubmed
But it's not as simple as just needing a TS test to determine if Alimta will work. For example, based on a foreign research study in a similar-but-different drug, I'd hypothesize (or speculate) that maybe dihydropyrimidine dehydrogenase (DPD) is another possible factor that might need to be considered along with TS. And DHFR & GARFT might be somehow involved in the mechanism of action, too.

_________________________________
Stage 4 ROS1+ [mucinous BAC] adenocarcinoma NSCLC since 2011
Xalkori (crizotinib) 5 yrs
Alimta (pemetrexed) + carboplatin (mere months)
TPX-0005 (repotrectinib) TBD (1+ years as of Fall 2018)

Dr West
Reply To: Alimta Sensitivity Correlates with Never- or Light

+++++++++++++++++++++++++
Dr. Howard (Jack) West
Associate Clinical Professor
Medical Oncology
City of Hope Cancer Center
Duarte, CA

Founder & President
Global Resource for Advancing
Cancer Education

craig
craig's picture
Reply To: Alimta Sensitivity Correlates with Never- or Light

DenderDender,

I've edited my prior reply after re-considering what you intended by your question.

But I also like Dr. West's answer if you are looking for info about trials that are testing whether TS status can help improve prediction of Alimta sensitivity or choice of treatment.

Best hopes,

Craig

_________________________________
Stage 4 ROS1+ [mucinous BAC] adenocarcinoma NSCLC since 2011
Xalkori (crizotinib) 5 yrs
Alimta (pemetrexed) + carboplatin (mere months)
TPX-0005 (repotrectinib) TBD (1+ years as of Fall 2018)